The cholesterol biosynthetic pathway is crucial for most eukaryotic cells. The key and rate-limiting enzyme of this metabolic pathway, the HMG-CoA reductase (HMGR), could play a pivotal role in brain physiology, since it leads to the production of isoprenoids crucial for several neuronal processes. In particular, prenyls serve as lipid attachments for proteins involved in synaptic transmission such as Rab3. Although clinical evidence suggests a close link between the inhibition of cholesterol biosynthetic pathway and some brain functions, studies on the behavioural consequences of this inhibition are currently limited and controversial and the molecular mechanisms are poorly understood.

Thus, the aim of this work was to investigate the role of HMGR in the modulation of emotional reactivity in rats analyzing both behavioural and molecular aspects.

To this aim, young male rats were chronically treated with a HMGR strong inhibitor, the simvastatin.

The principal obtained results showed:

- a decrease in the time and the frequency spent in the active social interaction, thus specifically inducing the occurrence of a social anxiety-related behaviour;

- a decrease of the active fraction of Rab3, which is strongly involved in synaptic vesicle release;

- a decrease in protein isoprenylation and, as a consequence, an enhanced degradation of Rab3.

These results demonstrate that HMGR-related pathway plays a crucial role in social behaviour probably through the modulation of an isoprenylated protein involved in synaptic transmission.